Pharmacokinetics and Exposure-Response Relationship of Teprotumumab, an Insulin-Like Growth Factor-1 Receptor-Blocking Antibody, in Thyroid Eye Disease

Abstract

Background and objective: Thyroid eye disease (TED) is characterized by inflammation/expansion of orbital tissues, proptosis, and diplopia. Teprotumumab is the first US Food and Drug Administration-approved therapy for TED, administered as an initial intravenous infusion of 10 mg/kg followed by 20 mg/kg every 3 weeks for an additional seven infusions. The objective of this article is to discuss the pharmacokinetics and exposure-response profile for teprotumumab in patients with TED.

Methods: A population pharmacokinetic analysis was performed to characterize pharmacokinetics and select dosing in patients with TED. Exposure-response was evaluated for efficacy (proptosis response, clinical activity score categorical response, and diplopia response) and safety (hyperglycemia, muscle spasms, and hearing impairment) parameters.

Results: Teprotumumab pharmacokinetics was linear in patients with TED, with low systemic clearance (0.334 L/day), low volume of distribution (3.9 and 4.2 L for the central and peripheral compartment, respectively), and a long elimination half-life (19.9 days). The approved dosing regimen provided > 20 µg/mL for > 90% insulin-like growth factor 1 receptor saturation throughout the dosing interval. Model-predicted mean (± standard deviation) steady-state area under the concentration-time curve, peak, and trough concentrations in patients with TED were 131 (± 30.9) mg∙h/mL, 643 (± 130) µg/mL, and 157 (± 50.6) µg/mL, respectively. Female patients had a 15% higher steady-state peak concentration but a similar steady-state area under the concentration-time curve vs male patients. No other covariates affected teprotumumab pharmacokinetics. No meaningful correlations between teprotumumab exposures and efficacy or safety parameters were observed.

Conclusions: Teprotumumab pharmacokinetics was well characterized in patients with TED, and generally consistent with other IgG1 antibodies. Efficacy was consistent across the exposure range with a well-tolerated safety profile supporting the current dose regimen for patients with TED.

Trial registration: ClinicalTrials.gov NCT00400361 NCT01868997 NCT03461211.

Conflict of interest statement

Yuying Gao and Fengyan Xu received consulting fees from Horizon Therapeutics; Yan Xin, Nivedita Bhatt, Jason Chamberlain, Saba Sile, Suzy Hammel, Robert J. Holt, Thompson, and Srini Ramanathan are employed by and own stocks in Horizon Therapeutics.

© 2021. The Author(s).

Figures

Fig. 1

Exposure-response relationship for key efficacy endpoints at week 24. Panel a, proptosis response; panel b, clinical activity score response; panel c, diplopia response. Open circles represent each subject’s exposure; lines represent median and interquartile ranges. AUCss steady-state area under the concentration–time curve, Cmax,ss steady-state peak concentration, Cmin,ss steady-state trough concentration

Fig. 2

Probability of proptosis response at week 24 vs steady-state trough concentration (Cmin,ss). Probability of proptosis response: = 1 for responder; = 0 for non-responder. The dark blue dashed line is the predicted probability by a linear logistic regression model. The shaded area is the 95% prediction interval based on 1000 bootstrap samples. The vertical light-blue dashed lines are the first quartile, median, and third quartile Cmin,ss (from left to right) following the teprotumumab regimen for thyroid eye disease. The open blue circles reflect the observed events. The filled black symbols are the observed probability of events and the error bars are SE [sqrt (P × (1 − P)/N)] for quantiles (at 100×(1/q)th percentiles, vertical dotted lines) of exposures (plotted at the median value within each quantile). Q3W every 3 weeks, Q4W every 4 weeks

Fig. 3

Lack of correlation between teprotumumab exposure and selected safety variables. a hyperglycemia; b muscle spasms; c hearing impairment. Open circles represent each subject’s exposure; lines represent median and interquartile ranges. AUCss steady-state area under the concentration–time curve, Cmax,ss steady-state peak concentration, Cmin,ss steady-state trough concentration